The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to be, or to describe, prior art to the invention. All publications are incorporated by reference in their entirety.
AraC is an analog of deoxycytidine, which is transported into cells via nucleoside transporters and phosphorylated to the active metabolite araC triphosphate (araCTP) by nucleoside and nucleotide kinases. It is one of the most-successful drugs used to treat acute nonlymphocytic leukemia, but it is ineffective in treatment against hepatocellular carcinoma (“HCC”) because the necessary nucleoside kinase are expressed at low levels in the liver (Arner et al. Pharmacol. Ther. 67(2):155-86, (1995); Ruiz van Haperen et al. Semin. Oncol. 22 Suppl 11(4):35-41, (1995)). However, the kinase remains highly expressed in the target organs of toxicity (e.g. bone marrow) which leads to the associated dose-limiting toxicities. Cyclic prodrugs of araC offer the potential to improve effectiveness of araC in the liver by specifically delivering higher concentrations of araCTP to CYP3A4-expressing liver and HCC cells. The delivery of araC as its monophosphate, araCMP, is expected to bypass limiting deoxycytidine kinase, deoxycytidine deaminase and transport activities in both normal and resistant tumor cells. AraCMP cyclic diesters of 1,3-propane diols are therefore predicted to have increased anti-tumor activity in the liver, compared to araC, with reduced toxicity to the extra-hepatic hematopoietic system, which leads to dose-limiting myelosuppresion seen in man (See U.S. Pat. No. 6,312,662).
Hepatitis and liver cancer remain poorly treated with current therapies due to dose-limiting extrahepatic side effects or inadequate delivery of chemotherapeutic agents to the target tissue. Limitation in present approaches include drug loading capacity, complexity of the manufacture and characterization of the conjugate, and receptor down regulation. Thus, there is still a need for a way to deliver drugs such as araC to the liver.